Whereas UDP-glucuronosyltransferase (UGT) isozymes conjugate numerous chemical toxins present in our daily diet and environment to glucuronic acid, special properties and the enzymatic mechanism(s) that enable endoplasmic reticulum (ER)-bound UGT isozymes to convert innumerable structurally diverse lipophiles to excretable glucuronides are unknown. We have accumulated evidence that phoshorylation of UGTs is critically important for their activity. Inhibition of in-cellulo UGT activities by treatment with various kinase inhibitors, incorporation of [33P] orthophosphate into immunoprecipitable UGT proteins and loss of UGT activities when their PKC and/or tyrosine kinase sites are mutated provide evidence that all UGTs undergo and require phosphorylation. Co-immunoprecipitation, co-localization via immunofluorescence and cross-linking studies demonstrate UGTs and certain kinase isozymes functionally share compartment(s) or complex structure(s). Substrate and pH changes following mutation of kinase site(s) in select UGTs indicate important functional role(s) for phosphorylated amino acid residues. While UGT1A isozymes analyzed, to date, require PKC-dependent phosphorylation, UGT2B7, the relevant isozyme that detoxifies endogenous genotoxic catechol-estrogens, requires tyrosine phosphorylation. Results in a number of studies indicate select tyrosine kinase (sTK) phosphorylates UGT2B7, including: (a) loss of activity following mutation of TK phosphorylation sites in 2B7, (b) loss of sTK pull-down with anti-UGT following mutation of sTK binding sites in 2B7, (c) enhancement of 2B7 activity and its Y438-phosphorylation status by co-transfection with wild-type or activated sTK, but not by dominant-negative sTK and (d) crosslinking of 2B7 and sTk, which was dissociated by pretreatment with sTK inhibitor. Moreover, 2B7 activity is associated with active sTK, and not total sTK, in 8 pairs of normal/tumor breast tissue sets, suggesting the capacity of 2B7 to detoxify catechol estrogens is dependent upon active sTK in breast tissues. Finally, we exploited UGT phosphorylation requirement to demonstrate glucuronidation can markedly compromise drug efficacy due to premature clearance and to determine whether inhibition of glucuronidation prior to administration of glucuronidatable drugs will lead to a significant increase in free drug uptake. After having established in cellulo that mouse recombinant UGTs also undergo phosphorylation, we pretreated antigen-stimulated mice with curcumin to target UGT phosphorylation before administration of immunosuppressant, mycophenolic acid (MPA). In-vivo downregulation of UGT phosphorylation caused a 6- to 8-fold increase in both free MPA in blood and immunosuppression. Widely used MPA for renal transplant patients demonstrates glucuronidation can markedly compromise drug efficacy and that transient downregulation of UGT phosphorylation can have a significant effect on efficacy of glucuronidatable drugs.